Oxaboroles and salts thereof, and their use as biocides

ABSTRACT

A method for the protection of a medium by susceptible to microbial attack by the treatment of the medium with an oxaborale or a salt of an oxaborale.

This application is the national phase of international applicationPCT/GB95/01206 filed May 26, 1995 which designated the U.S.

The present invention relates to the use of oxaboroles and salts thereofas industrial biocides, especially fungicides, biocidal compositionscontaining the oxaboroles including their salts and certain oxaboroles.

No single industrial biocide is ideal for all applications and newbiocides are constantly being sought with better activity againstindividual spoilage micro-organisms, wider spectrum of activity,improved compatibility with the medium in which they are used andimproved persistence in use. Safety in use is another importantconsideration.

A small number of compounds containing an oxaborole ring (hereinafter"oxaborole") have already been described in the literature. These areN-(1,3-dihydro-1-hydroxy-2,1-benzoxaborol-6-yl)-succinamic acid (CA 5523423c); 4-(1,3-dihydro-1-hydroxy-2,1-benzoxaborol-6-ylazo)-2-naphthoicacid (CA 55 23423c); 1,3-dihydro-1-hydroxy-6-nitro-2,1-benzoxaborole (CA55 23423b); 6-amino-1,3-dihydro-1-hydroxy-2,1-benzoxaborole and itshydrochloride (CA 55 23423c);1,3-dihydro-1-hydroxy-7-methyl-2,1-benzoxaborole (CA 55 6473f);1-(benzyloxy)-1,3-dihydro-2,1-benzoxaborole (CA 61 16084f);1,3-dihydro-1-hydroxy-N,N-dimethyl-2,1-benzoxaborol-6-amine (CA 1(3)22633f); 4-bromo-1,3-dihydro-1-hydroxy-2,1-benzoxaborole (CA 1(3)22633f); 1,1'-oxybis 4-bromo-1,3-dihydro-2,1-benzoxaborole (CA 1(3)22633f); 1-(cyclohexyloxy)-1,3-dihydro-2,1-benzoxaborole (CA 61 16084f);1-ethoxy-1,3-dihydro-2,1-benzoxaborole (CA 61 16084f);3,7-dihydro-1,5-dihydroxy-1H, 3H-benzo 1,2-c: 4,5-c'!bis 1,2!oxaborole(CA 61 14698a); 1,3-dihydro-1-hydroxy-6-methyl-2,1-benzoxaborole (CA 6114698b); 5-bromo-1,3-dihydro-1-hydroxy-2,1-benzoxaborole-6-methanol (CA51 14698b); 1,1'-oxybis 1,3-dihydro-2,1-benzoxaborole!(CA 103(3)22633f); and boronophthalide (CA 116(13) 129587q). French certificate ofutility No 73 29370 discloses boronophthalide(1-hydroxy-3H-1,2-benzoxaborole) and this is the only citation knownwhich discloses that an oxaborole is biologically active. It isdisclosed as being useful in inhibiting the growth of micro organisms inaviation fuels. However, at least 100 ppm of the boronophthalide isrequired to protect the fuel.

It has now been found that compounds containing an oxaborole ring areparticularly effective against micro-organisms such as bacteria, algae,yeasts and particularly fungi, especially fungi which cause degradationof plastics materials. The level of microbiological activity now foundis surprising in the light of the disclosure in the above utilitycertificate.

According to the present invention there is provided a method for theprotection of a medium susceptible to microbial attack by the treatmentof the medium with an effective amount of an oxaborole of generalformula (1) ##STR1## or a salt thereof wherein

A and D are each independently, hydrogen, optionally substituted C₁₋₈-alkyl, aralkyl, aryl, or heterocyclyl or where A and D together withthe carbon atoms to which they are attached form a 5,6 or 7-memberedfused ring which itself may be substituted;

X is a group --CR¹ R² wherein R¹ and R² are each, independently,hydrogen, optionally substituted C₁₋₆ -alkyl, nitrile, nitro, aryl oraralkyl or R¹ and R² together with the carbon atom to which they areattached form an alicyclic ring;

R is hydrogen, optionally substituted C₁₋₈ -alkyl, aralkyl, aryl,heteroaryl, cycloalkyl or a radical of formula (2) ##STR2## wherein A, Dand X are as hereinbefore defined except where the medium is aviationfuel and the only oxaborole is boronophthalide.

When A and/or D is alkyl, it may be linear or branched and is preferablyC₁₋₁₂ -, more preferably C₁₋₈ - and especially C₁₋₄ -alkyl.

When A and/or D is substituted alkyl, the substituent may be C₁₋₆-alkoxy, hydroxy, halogen, nitrile, amino, substituted amino, carboxy,acyl, aryloxy or carbonylamnino optionally substituted by C₁₋₆ -alkyl.

When A and/or D is alkyl the alkyl group or groups are preferablyunsubstituted.

When A and/or D is aryl, it is preferably phenyl which may itself besubstituted.

When A and/or D is aralkyl, it is preferably benzyl or 2-ethylphenyl,where the phenyl ring may be substituted. w hen the phenyl ring issubstituted, the substituents include C₁₋₆ -alkyl, C₁₋₆ -alkoxy,aryloxy, hydroxy, halogen, nitro, carbonamido, sulphonamido,trifluoromethyl or amino optionally substituted by one or more C₁₋₆-alkyl groups.

Aryloxy is preferably phenoxy.

When A and D together with the two carbon atoms to which they areattached form a fused ring the ring may be alicyclic as in cyclopentene,cyclohexene or cycloheptene or it may be aromatic such as phenyl,pyridyl, thienyl or furanyl. The fused ring may also carry substituentsas described hereinbefore for substituted phenyl and substituted alkyl.The fused ring may also contain more than one ring system, for example,a naphthyl or quinolinyl ring system or the fused ring may also link twooxaborole rings as for example in 1H, 3H-benzo 1,2-c: 4,5-c'!bis1,2!oxaborole.

When R¹ and/or R² is aryl it is preferably phenyl.

When R¹ and/or R² is aralkyl it is preferably benzyl.

Preferably, at least one of R¹ and R² is hydrogen and it is especiallypreferred that both are hydrogen.

When R is alkyl it may be linear or branched and is preferably C₁₋₁₂ -and especially C₁₋₆ -alkyl.

When R is substituted alkyl, the substitutent may be C₁₋₆ -alkoxy, C₁₋₆-alkylthio, hydroxy, amino, substituted amino, carboxy, aryl, aryloxy,carbonamido optionally substituted by C₁₋₆ -alkyl, aryl such as phenyland aralkyl such as benzyl.

When R is aralkyl it is preferably benzyl or 2-ethylphenyl.

When R is aryl it is preferably phenyl.

When R is heteroaryl it is preferably quinolinyl and particularlyquinolin-8-yl.

When R is cycloalkyl it is preferably cyclohexyl.

When the substituent is halogen, it is preferably bromine, chlorine andespecially fluorine.

One preferred class of oxaborole is a benzoxaborole of formula 1 whereinA and D together with the carbon atoms to which they are attached form afused phenyl, naphthyl or thienyl ring.

When the fused ring is phenyl, the oxaborole is a benzoxaborole and thesubstituent or substituents may be in any of positions 4,5,6 or 7 of thebenzoxaborole. Preferably the substituent or substituents is/are in the5 and/or 6 position. Preferred substituents are amino, alkyl, alkoxy,phenyl, phenoxy, sulphonamide, carbonamide, each of which may besubstituted, and also trifluoromethyl, chlorine, bromine and especiallyfluorine.

When the fused ring is naphthyl, the other fused phenyl ring is attachedto the benzoxaborole ring system in either the 4,5- or 5,6-position.

In one preferred class of oxaborole, R is hydrogen.

Another preferred class of oxaboroles for use in the present inventionis where R is substituted alkyl, especially where the substituent is aprimary, secondary or tertiary amino group and particularly wherein thealkylene amino group forms a 5-, 6- or 7-membered ring together with theboron atom and the oxygen atom to which the group R is attached. Suchcompounds are esters containing a tetrahedral boron atom as for examplein formula (3) below ##STR3## wherein A,D and X are as definedhereinbefore;

R³ and R⁴ are each independently, hydrogen, optionally substituted C₁₋₁₈-alkyl or optionally substituted phenyl or R³ together with Y or part ofY forms a 5- or 6- or 7-membered optionally substituted ring containingthe nitrogen atom; and

Y is an optionally substituted divalent alkylene linking groupcontaining up to 18 carbon atoms.

R³ and R⁴ are preferably optionally substituted C₁₋₁₂ -alkyl, morepreferably optionally substituted C₁₋₈ -alkyl and especially substitutedC₁₋₆ -alkyl.

It is preferred that when R³ and/or R⁴ is alkyl the alkyl group isunsubstituted.

The alkylene group represented by Y may be linear or branched.

When Y is substituted alkylene the substituent is preferably phenyl,C₁₋₆ -alkoxy, C₁₋₆ -alkylthio or carbonyl alkylene as for example a--COCH₂ -- group.

When Y or part of Y forms a 5-, 6- or 7-membered optionally substitutedring the substituent may be a fused ring which may itself besubstituted.

Preferably Y is unsubstituted alkylene.

When R³ together with Y forms a 6-membered optionally substituted ringthe ring is preferably a quinolinyl ring as obtainable, for example,from 8-hydroxyquinoline.

When R³ together with part of Y forms a 5-membered ring the ring ispreferably pyrrolidin-2-yl.

It is preferred that A and D together with the carbon atoms to whichthey are attached form an aromatic ring or ring system such as forexample a fused phenyl, thienyl or naphthyl ring which ring or ringsystem may be substituted as defined hereinbefore for substituted phenyland substituted alkyl.

When A and D together with the carbon atoms to which they are attachedform a fused phenyl ring which is substituted, the oxaborole may be a1H, 3H-benzo 1,2-c:4,5-c'! bis 1,2! oxaborole containing an ester groupattached to each boron atom.

A particularly preferred class of oxaborole of formula 3 is that offormula 4 ##STR4## wherein A, D and X are as defined hereinbefore;

n is 1, 2 or 3;

R³ is hydrogen, optionally substituted C₁₋₁₈ -alkyl or optionallysubstituted phenyl;

R⁵ and R⁶ are each independently, hydrogen, optionally substituted alkylcontaining up to a total of 16 carbon atoms or optionally substitutedphenyl.

Preferably R⁵ and R⁶ are each, independently, optionally substitutedC₁₋₆ - and especially optionally substituted C₁₋₄ -alkyl.

Preferably two of R³, R⁵ and R⁶ are hydrogen. It is especially preferredthat R⁵ and R⁶ are both hydrogen.

Preferably n is 1 or 2 and especially 1.

When A and/or D and/or R is a group which is or contains halogen thehalogen may be fluorine, chlorine, bromine or iodine. When A and/or D isalkyl substituted by halogen, it may contain more than one halogen atomas in trifluoromethyl.

When A and D together with the two carbon atoms to which they. areattached form a fused ring, any substituent in the fused ring ispreferably attached to a carbon atom other than that adjacent to theoxaborole ring. Thus in the case of 1,2-dihydro-2,1-benzoxaboroles thesubstituent or substituents are preferably in the 5 and/or 6 position.

When the oxaborole of formula 1 is a salt, the group --OR attached tothe boron atom is ionic as in --O⁻ R⁺ where R⁺ is an alkali metal suchas lithium, potassium or sodium or R⁺ is an amine salt or quaternaryammonium cation. In the latter case the quaternary ammonium ion mayitself be microbiologically active.

When A and/or D is amino or substituted amino, or when A and/or D and/orR contains amino or substituted amino the salt of the oxaborole offormula I may be the salt of an organic or inorganic acid. Examples ofsuch acids are acetic and hydrochloric acids.

Particularly useful effects have been obtained in plastics materials andpaint films where the compound containing an oxaborole ring isbenzoxaborole or the 6-chloro-, 5-chloro-, 5-fluoro- or5-bromo-derivative thereof and the oxaborole esters obtainable therefromby reaction with alkanoamines such as ethanolamine, 3-aminopropanol and4-aminobutanol.

The oxaborole may be used in undiluted form but is preferably formulatedin a composition together with a carrier. Thus, as a further aspect ofthe invention there is provided a composition comprising-a carrier andan oxaborole of general formula (1) or a salt thereof (hereinafter"biocide composition") with the proviso that when boronophthalide is theonly oxaborole present the carrier is not an aviation fuel.

The carrier may be a material which shows little, if any, antimicrobialactivity and may be, or include,, a medium which is susceptible to thegrowth of micro-organisms, such as bacteria or fungi. The carrier may bea solid but is preferably a liquid-medium and the biocide composition ispreferably a solution, suspension or emulsion of the oxaborole in aliquid medium.

The carrier is generally selected so that the biocide composition iscompatible with-the medium to be protected. Thus, for example, if themedium to be protected is a solvent-based paint, lacquer or varnish thecarrier is preferably a solvent, especially a non-polar solvent such aswhite spirits.

If the medium to be protected is a plastics material, the carrier ispreferably a plasticiser or stabiliser typically used in the fabricationof plastics articles such as dioctylphthalate, dioctyladipate orepoxidised soya bean oil. If the medium to be protected is an aqueousmedium, the carrier is preferably water or a water-miscible organicsolvent or mixture thereof. Examples of suitable water-miscible organicsolvents are acetic acid, N,N-dimethylformamide, dimethylsulphoxide,N-methyl-2-pyrrolidine, alcohols such as ethanol or glycols such asethylene glycol, propylene glycol and dipropylene glycol and lower C₁₋₄-alkyl carbitols such as methyl carbitol. If the carrier is a solid, thecomposition may be a dry solid as described in EP 407024.

If the biocide composition is in the form of a suspension or emulsion,it preferably also contains a surface active agent to produce a stabledispersion or to maintain the non-continuous phase uniformly distributedthroughout the continuous phase. Any surface active agent which does notadversely affect the biocidal activity of the compound of formula I maybe used, for example alkylene oxide adducts of fatty alcohols, alkylphenols, amines such as ethylene diamine and anionic surfactants such asadducts of naphthol sulphonates and formaldehyde.

The concentration of the oxaborole in the biocide composition ispreferably up to a level at which the biocide composition is stableunder the conditions of storage or transportation and is preferably from1 to 50%, especially from 5 to 30% and more especially from 10 to 20% byweight relative to the total weight of the biocide composition.

As noted hereinbefore, many of the oxaboroles are new.

According to a further aspect of the invention there is provided acompound of formula (1) ##STR5## or a salt thereof

wherein A, D, X and R are all as hereinbefore defined except forN-(1,3-dihydro-l-hydroxy-2,1-benzoxaborol-6-yl)-succinamic acid;6-nitro-, 6-amino-, 7-methyl-, 6-(NN-dimethylamino)-,5-(NN-dimethylamino)-, 4-bromo-, 6-methyl-,5-bromo-6-methylol-1,3-dihydro-1-hydroxy-2,1-benzoxaborole;boronophthalide; 1-benzyloxy-, 1-cyclohexyloxy-,1-ethoxy-1,3-dihydro-2,1-benzoxaborole; 1,1'-oxybis1,3-dihydro-2,1-benzoxaborole!; 1,1'-oxybis4-bromo-1,3-dihydro-2,1-benzoxaborole! and 3,7-dihydro-1,5-dihydroxy-1H,3H-benzo 1,2-c: 4,5-c'!bis 1,2!oxaborole.

Preferably A and D together with the carbon atoms to which they areattached form a fused phenyl ring which may itself be substituted asdefined hereinbefore and preferably R is hydrogen or alkyl substitutedby amino. It is also preferred that X is --CH₂ --.

Preferably the fused phenyl ring contains a halogen atom in the 5 and/or6 position of a benzoxaborole ring system, especially in the 5-position.Preferred halogens are fluorine and chlorine. Examples include 5-chloroand especially 5-fluoro benzoxaborole.

Other preferred oxaboroles are the O-esters obtainable by reacting theoxaborole with an aminoaliphatic carboxylic acid such as glycine or analkanolamine such as ethanolamine, 3-aminopropanol or 4-aminobutanol.

According to a further aspect of the invention there is provided acompound of formula 3 ##STR6## wherein A,D and X are as definedhereinbefore;

R³ and R⁴ are each, independently, hydrogen, optionally substitutedC₁₋₁₈ -alkyl or optionally substituted phenyl or R³ together with Y orpart of Y forms a 5-, 6- or 7-membered ring containing the nitrogenatom; and

Y is an optionally substituted divalent alkylene linking groupcontaining up to 18 carbon atoms.

The oxaboroles may be made by any method known to the art. Thus, the1,3-dihydro-l-hydroxy-2,1-benzoxaboroles may be made by reacting anortho-toluidine under Sandmeyer conditions to obtain an o-substitutedhalogeno toluene which is then reacted with magnesium or alkyl lithiumsuch as butyl lithium in an inert solvent and the Grignard reagent oraryl lithium so formed is reacted with a borate ester such as tributylborate to obtain a toluene boronic acid. This boronic acid is thenreacted with a brominating agent such as N-bromosuccinimide in an inertsolvent such as carbon tetrachloride to give a bromomethylbenzeneboronic acid which is hydrolysed in alkali to give the hydroxymethylanalogue which is finally cyclised to give the benzoxaborole under acidconditions. This is method A. The preparation ofo-bromomethylbenzeneboronic acids is described in JACS 1958 80 835.

Alternatively, an appropriate benzaldehyde is reacted withp-toluenesulphonylhydrazide in an inert solvent such as drydichloromethane and the product is subsequently reacted with borontribromide in the presence of a catalyst such as ferric or aluminiumchloride and then cyclised to give a1,2-dihydro-l-hydroxy-2-(4-methylphenyl-sulphonyl)-2,3,1-benzodiazaborine.This is subsequently hydrolysed under alkaline conditions and thenconverted to the benzoxaborole under acid conditions. It is generallynot necessary to isolate the intermediate diazaborine. This is method Band is described in Liebigs Ann. Chem. 1985 683.

Oxaboroles containing a fused aromatic ring can be made by reacting anaromatic compound containing a --CH₂ OH group with alkyl or aryl lithiumand an organoborate in a dry inert organic liquid.

According to a still further aspect of the invention there is provided aprocess for making an oxaborole containing a fused aromatic ring whichcomprises reacting an aromatic compound containing a --CH₂ OH group withalkyl or aryl-lithium and an organo-borate in a dry inert organicliquid.

Preferably the fused aromatic ring is a fused phenyl ring and thearomatic compound containing a --CH₂ OH group is an optionallysubstituted benzyl alcohol.

Preferably the aromatic compound containing a --CH₂ OH group alsocontains one or more further substitutents which are ortho-lithiationactivating groups since these allow for reaction under milderconditions. Such activating groups are preferably located in aposition(s) other than ortho to the --CH₂ OH group. Examples ofactivating groups are C₁₋₆ -alkoxy, halogen such as chlorine andfluorine, substituted alkyl such as --CH₂ OCH₃, --CH₂ NT₂, --CH₂ CH₂NT₂, substituted amino such as --NT₂, --NHCOT, --NHCO₂ T and amides suchas --SO₂ NHT, --SO₂ NT₂, --CONHT and --CONT₂ where T is aryl or alkyl.Preferably when T is aryl it is phenyl, and it is preferred that when Tis alkyl it is C₁₋₆ -alkyl.

An alkyl lithium compound is preferred which may be linear or branchedand is preferably C₁₋₆ -alkyl and especially C₁₋₄ -alkyl such as butyllithium.

The organic liquid is preferably an alkyl ether such as diethylether orpreferably a cyclic-ether such as tetrahydrofuran.

The reaction may be carried out at temperatures up to the boiling pointof the organic liquid. However, when the aromatic compound containing a--CH₂ OH group also contains an ortho-lithiation activating group thereaction is preferably carried out below 0° C. and more preferably below-50° C. It is especially preferred that the reaction is carried outbetween -70° and -100° C.

The aromatic compound containing a --CH₂ OH group may also carry furthersubstitutents which do not react with the alkyl or aryl lithiumcompound.

The organo-borate is preferably an alkyl borate which may be linear orbranched, more preferably a C₁₋₆ -alkyl and especially a C₁₋₄ -alkylborate.

sec-Butyl lithium and n-butyl borate are preferred.

The reaction between the aromatic compound containing a --CH₂ OH groupand alkyl or aryl lithium is preferably carried out in the presence of achelating agent. The preferred chelating agent istetramethyleneethylenediamine.

Oxaboroles containing a fused aromatic ring can also be made by reactingan aromatic compound containing a --CH₂ OH group and an ortho iodo orbromo group with alkyl or aryl lithium and an organo-borate.

According to a still further aspect of the invention there is provided aprocess for making an oxaborole containing a fused aromatic ringcomprising reacting an aromatic compound containing a -CH₂ OH group andan ortho iodo or bromo group with alkyl or aryl lithium and anorgano-borate in an inert organic liquid.

Preferred reaction conditions are as defined for the aromatic compoundcontaining a --CH₂ OH group.

The boron esters of the oxaborole are typically made by reaction of anoxaborole of formula 1 where R is hydrogen with an appropriateamino-aliphatic carboxylic acid or preferably an alkanolamine in aninert solvent at 25°-125° C. when the boron ester is formed almostinstantaneously. Preferably the inert solvent forms an azeotrope withwater to facilitate removal of water formed when the alkanolamine isreacted with the oxaborole. It is especially preferred that the solventis toluene. This is method C.

The oxaborole or compositions containing the oxaborole can be used forthe treatment of various media to inhibit the growth of micro-organismsand are especially effective in providing anti-fungal activity.

As a further aspect of the present invention there is provided a methodfor inhibiting the growth of micro-organisms on, or in, a medium whichcomprises treating the medium with an oxaborole or a biocide compositioncontaining an oxaborole.

The oxaborole can be used in conditions in which micro-organisms growand cause problems. Systems in which micro-organisms cause problemsinclude liquid, particularly aqueous, systems such as cooling waterliquors, paper mill liquors, metal working fluids, geological drillinglubricants, polymer emulsions and especially surface coatingcompositions such as paints, varnishes and lacquers and more especiallysolid materials such as wood, plastics materials and leather.

The oxaboroles have been found particularly effective in inhibitingmicrobial degradation of plastics materials such as plasticised PVC andurethanes since they are not significantly adversely affected by thehigh temperatures commonly used in the fabrication of such articles. Inthis respect the benzoxazoles have been found especially effective,particularly those containing one or more halogen substituents in thefused phenyl ring of the benzoxaborole.

The oxaborole can be included in such materials to provide ananti-microbial effect. The amount of the compound is typically in therange from 0.00001 to 2.0% preferably from 0.0001 to 1% and especiallyfrom 0.0002 to 0.5% by weight of the compound relative to the system towhich it is added. In certain cases, microbial inhibition has beenobtained with from 0.0005% to 0.01% by weight of the oxaborole. Thus, inthe case of plastics materials the oxaboroles have been found to inhibitmicrobial growth at an applied concentration of less than 0.05%,particularly less than 0.01% and especially less than 0.005% and moreespecially less than 0.001%.

The oxaborole may be the only antimicrobial compound used to protect themedium or it may be used together with one or more different oxaborolesor with one or more other compounds having antimicrobial activity. Amixture of anti-microbial compounds hereinafter referred to as a"biocide mixture" often has a broader anti-microbial spectrum and henceis more generally effective than the components of the mixture. Theother antimicrobial compound or compounds may possess anti-bacterial,anti-fungal, anti-algal or other antimicrobial activity. The biocidemixture typically contains from 1 to 99% by weight, and preferably from40 to 60% by weight, of an oxaborole relative to the total weight of anantimicrobially active compound, in the biocide mixture.

Examples of other antimicrobial compounds which may be used, togetherwith the oxaborole are quaternary ammonium compounds such asN,N-diethyl-N-dodecyl-N-benzylammonium chloride;N,N-dimethyl-N-octadecyl-N-(dimethylbenzyl)ammonium chloride;N,N-dimethyl-N,N-didecylammonium chloride;N,N-dimethyl-N,N-didodecylammonium chloride;N,N,N-trimethyl-N-tetradecylammonium chloride;N-benzyl-N,N-dimethyl-N(C₁₂ -C₁₈ -alkyl)ammonium chloride;N-(dichlorobenzyl)-N,N-dimethyl-N-dodecylammonium chloride;N-hexadecylpyridinium chloride; N-hexadecylpyridinium bromide;N-hexadecyl-N,N,N-trimethylammonium bromide; N-dodecylpyridiniumchloride; N-dodecylpyridinium bisulphate;N-benzyl-N-dodecyl-N,N-bis(beta-hydroxyethyl)ammonium chloride;N-dodecyl-N-benzyl-N,N-dimethylammonium chloride;N-benzyl-N,N-dimethyl-N-(C₁₂ -C₁₈ -alkyl)ammonium chloride;N-dodecyl-N,N-dimethyl-N-ethylammonium ethylsulphate;N-dodecyl-N,N-dimethyl-N-(1-naphthylmethyl)ammonium chloride;N-hexadecyl-N,N-dimethyl-N-benzylammonium chloride;N-dodecyl-N,N-dimethyl-N-benzylammonium chloride and1-(3-chloroallyl)-3,5,7-triaza-1-azonia-adamantane chloride; ureaderivatives such as 1,3-bis(hydroxymethyl)-5,5-dimethylhydantoin;bis(hydroxymethyl)urea; 3-(3,4-dichlorcphenyl)-1,1-dimethylurea;3-(4-isopropylphenyl)-1,1-dimethylurea; tetrakis(hydroxy-methyl)acetylene diurea;1-(hydroxymethyl)-5,5-dimethylhydantoin and imidazolidinylurea; aminocompounds such as1,3-bis(2-ethyl-hexyl)-5-methyl-5-amino-hexahydropyrimidine;hexamethylenetetramine; 1,3-bis(4-amino-phenoxy)propane; and 2-(hydroxymethyl)-amino!ethanol; imidazole derivatives such as 12-(2,4-dichloro-phenyl)-2-(2-propenyloxy)ethyl!-1H-imidazole;2-(methoxycarbonyl-amino)-benzimidazol;1-decyl-3-dodecyl-2-methylimidazolium bromide;dodecylbis(1-decyl-2-methyl-imidazolium)-dibromide; nitrile compoundssuch as 2-bromo-2-bromomethyl-glutaronitrile,2-chloro-2-chloromethylglutaronitrile;2,4,5,6-tetra-chloroisophthalodinitrile; thiocyanate derivatives such asmethylene(bis)thiocyanate; tin compounds or complexes such astributyltinoxide, chloride, naphthoate, benzoate or 2-hydroxybenzoate;isothiazolin-3-ones such as 4,5-trimethylene-4-isothiazolin-3-one,2-methyl-4,5-trimethylene-4-isothiazolin-3-one,2-methylisothiazolin-3-one, 5-chloro-2-methyl-isothiazolin-3-one,benzisothiazolin-3-one; 2-methylbenzisothiazolin-3-one,2-octylisothiazolin-3-one, 4,5-dichloro-2-octylisothiazolin-3-one;N-(2-ethylbutyl)benzisothiazolin-3-one);N-(n-hexyl)benzisothiazolin-3-one; thiazole derivatives such as2-(thiocyanomethylthio)-benzthiazole and mercaptobenzthiazole; nitrocompounds such as tris(hydroxymethyl)nitromethane;5-bromo-5-nitro-1,3-dioxane and 2-bromo-2-nitropropane-1,3-diol; iodinecompounds such as iodo propynyl butyl carbamate and tri-iodo allylalcohol; aldehydes and derivatives such as glutaraldehyde (pentanedial),p-chlorophenyl-3-iodopropargyl hemiformal, formaldehyde and glyoxal;amides such as chloracetamide; N,N-bis(hydroxymethyl)chloracetamide;N-hydroxymethyl-chloracetamide and dithio-2,2-bis(benzmethyl amide);guanidine derivatives such as poly(hexamethylenebiguanide) and1,6-hexamethylene-bis 5-(4-chlorophenyl)biguanide!; imidazolium halidessuch as N,N'-didecyl-2-methylimidazolium bromide and1,12-bis-(N-decyl-2-methylimidazolium)-dodecyl dibromide; thiones suchas 3,5-dimethyltetrahydro-1,3,5-2H-thiodiazine-2-thione; triazinederivatives such as hexahydrotriazine and1,3,5-tri-(hydroxyethyl)-1,3,5-hexahydrotriazine,6-chloro-2,4-diethylamino-s-triazine and4-cyclopropylamino-2-methylthio-6-t-butylamino-s-triazine; oxazolidineand derivatives thereof such as bis-oxazolidine; furan and derivativesthereof such as 2,5-dihydro-2,5-dialkoxy-2,5-dialkylfuran; carboxylicacids and the salts and esters thereof such as sorbic acid and4-hydroxybenzoic acid and their salts and esters; phenol and derivativesthereof such as 5-chloro-2-(2,4-dichloro-phenoxy)phenol;thio-bis(4-chlorophenol) and 2-phenylphenol; sulphone derivatives suchas diiodomethyl-paratolyl sulphone;2,3,5,6-tetrachloro-4-(methylsulphonyl)pyridine and hexachlorodimethylsulphone; thioamides such as dimethyldithiocarbamate and its metalcomplexes, ethylenebisdithiocarbamate and its metal complexes, and2-mecaptopyridine-N-oxide and its metal complexes and imides such astrichloromethylmercaptophthalimide,fluorodichloromethylmercaptophthalimide, andtrichloromethylmercaptotetrahydrophthalimide.

Further aspects of the present invention are described in the followingillustrative examples in which all preparative details are given inparts by weight unless otherwise stated. The compounds were evaluatedfor their antimicrobial properties under sterile conditions using thetest protocols described below.

Microtitre Screen Protocol for determining MIC For bacteria

An overnight culture (18 hours; 37° C.) of the appropriatemicro-organism was prepared in nutrient broth to give approximately 10⁹viable cells per 1 ml of culture. 20 μl of the culture was thentransferred aseptically to 20 ml of the nutrient broth. 200 μl of thisinoculum was then added to all vertical wells of a microtitre plate and100 μl inoculum added to each subsequent row of vertical wells.

A 5000 ppm solution of the chemical under test was prepared in anappropriate solvent of which 20 μl was added to the first well of thesecond row of vertical wells to act as control. The contents of eachwell were mixed, 100 μl withdrawn and transferred to adjacent horizontalwells in that row. This process was repeated across each vertical row ofwells to give a serial dilution of each compound under test ranging from500 ppm to 0.25 ppm. The microtitre plate was then sealed and incubatedat 25° C. for 42-48 hours. The minimum inhibitory concentration (MIC)was indicated by the well with lowest concentration showing no visiblebacterial growth.

For Saccharomyces Cerevisiae

The culture was prepared as for bacteria except that Oxoid Malt brothwas substituted for nutrient broth. Incubation was for 42 to 72 hours at30° C.

For Fungi

The fungi were grown on a malt agar plate for one week at 25° C. andflooded with 2ml of sterile saline. Spores were released by carefulagitation using a sterile loop. The spore suspension was poured into aGlass 25 ml Universal bottle. (Spore count approx 10⁷ ml⁻¹).

20 μl of the spore suspension was then added to 20 ml of malt broth andused to inoculate the microtitre plate. Dilutions were as described forthe bacterial MIC and incubation was for 42-72 hours at 25° C.

Paint Film Protocol

This is identical to the Microtitre screen protocol except that theplates were incubated for 4 days and the organisms used were fungi thathad been isolated from deteriorated paint film surfaces, namely

Alternaria alternata (AA) PRA FS 4

Aureobasidium pullulans (AP) PRS FS 1

Cladosporium herbarum (CH) CMI 16203

Phoma violacia (PV) PRA FS 13

Stemphylium dendriticum (SD) PRA FS 15

EXAMPLE 1 Preparation of5-chloro-1,3-dihydro-1-hydroxy-2,1-benzoxaborole (Method B)

a) Preparation of 3-chlorobenzaldehyde tosyl hydrazide

A solution of 3-chlorobenzaldehyde (15.56 parts; 0.109M; Aldrich) inmethylated spirits (40 ml) was added slowly at below 10° C. to a stirredsuspension of p-toluene-sulphonylhydrazide (20.7 parts; 0.108M) inmethylated spirits (150 ml). The reaction mass was then stirred at 20°to 25° C. for 1 hour and then heated at 60°-70° C. for 11/2 hours whenthe reactants and products dissolved. The solvent was then removed byrotary evaporation and the product was obtained as a solid which wasslurried with ether and washed with n-hexane. Yield=27.2 parts (81.5%theory) mpt 122°-3° C.

Elemental analysis

Theory 54.5%C; 4.2%H; 9.1%N

Found 54.5%C; 4.3%H; 9.1%N

Proton NMR (CDCl₃ :ppm)

8.5, s, 1H(--NH--); 7.9, d, 2H(Tosyl aromatic); 7.7,s, 1H(CH═N); 7.5, s,1H(aromatic); 7.2-7.4, m, 5H(Tosyl aromatic); 2.3, s, 3H(--CH₃)

b) Preparation of title compound

A suspension of anhydrous ferric chloride catalyst (0.75 parts, Fisons)in dry dichloromethane (20 ml) was added at 20° to 25° C. simultaneouslywith boron tribromide (25 parts, 0.1M, Aldrich) in dry dichloromethane(100 mls) to a stirred suspension of the hydrazide from a) above (10.18part, 0.033M) in dry dichloromethane (160 mls) under a nitrogen blanket.The reactants were then stirred under reflux and the evolved hydrogenbromide trapped under aqueous sodium hydroxide. After 3 hours stirringat reflux, the reactants were allowed to stand at 20°-25° C. for 48hours and then stirred under reflux for a further 4 hours. The reactionmass was then cooled and the solvent removed by rotary evaporation. Thesolid obtained was then stirred under reflux with 2N sodium hydroxidesolution (160 ml) for 3 hours. The brown aqueous suspension wasextracted with dichloromethane (50 ml), screened and then acidified toabout pH 2 by addition of 2N hydrochloric acid. The solid was filtered,slurried with dichloromethane (400 ml) and then washed with a saturatedsolution of sodium bicarbonate followed by water. Yield=24 parts (43%theory). The solid was slurried in hot dichloromethane and filtered togive 0.36 parts oxaborole mp 140°-45° C. The dichloromethane solutionwas cooled and the solid filtered giving a further 0.35 parts oxaborolemp 146°-8° C. The solids were combined and recrystallised frommethylated spirits.

Yield=0.51 parts (9.2% theory) mp 150°-4° C.

Elemental Analysis

Theory 49.8%C, 3.5%H, 21.06%Cl

Found 49.5%C, 3.5%H, 21.0%Cl

Proton NMR (CDCl₃) ppm

9.3, s, 1H(--OH); 7.5, d, s, d, 3H(aromatic); 5.0, s, 2H(--CH₂ --O).

EXAMPLE 2 Preparation of the ethanolamine ester of boronophthalide(Method C)

Boronophthalide (0.22 part, 0.00164M) was dissolved in toluene (40 ml)at 80° C. and ethanolamine (0.1 part, 0.00164M) added slowly. The esterformed immediately. Toluene (50 ml) was added, and the reactants heatedto reflux to dissolve the ester. After screening, the product separatedon cooling as a pale solid 0.15 part (52% theory) mp 214°-216° C.

Elemental Analysis

Theory 61%C, 6.8%H, 7.9N

Found 60.3%C, 6.7%H, 7.6%N

EXAMPLE 3 Preparation of 3-aminopropanol ester of boronophthalide

This was prepared as described in example 2 but using boronophthalide(0.15 part, 0.00112M) and 3-aminopropanol (0.084 part, 0.00112M,Aldrich). The product was obtained as a colourless solid byrecrystallisation from toluene/100°-120° C. petroleum ether.

Yield=0.18 part (84% theory) mp=174°-6° C.

Elemental Analysis

Theory 62.80C; 7.3%H; 7.3%N

Found 64.5%C; 7.5%H; 7.1%N

EXAMPLES 4-14

The MIC of the following boronophthalide derivatives was determinedusing the microtitre screen protocol described hereinbefore.

In these examples two fungi and two bacteria were used namelySaccharomyces cerevisiae NCYC 124 (SC), Asperaillus niger CMI 17454(AN), Pseudomonas aeruginosa NCIB 10421 (PA) and Staphylococcus aureusNCIB 9518 (SA).

The results are given in Table 1 below.

                  TABLE 1    ______________________________________                MIC date (ppm) organism    Example           Substituent                      SC       AN      PA    SA    ______________________________________    4      --         0.5      0.25    >50   62    5      6 Cl--     2        2       N     62    6      5 PhO--    31       16      N     31    7      5 tert Bu--                      125      62      N     31    8      5 F--      <0.25    <0.25   125   31    9      5,6 fused Ph                      31       16      N     16    10     4,5 fused Ph                      16       16      N     62    11     3 Ph--     16       31      N     125    12     5 Cl--     0.5      <0.25   N     62    13     5 CF.sub.3 --                      8        0.25-0.5                                       125   62    14     5 Br--     8        1       N     125    ______________________________________     Footnote to Table 1     N = No activity at 100 ppm level     SC, AN, PA, SA are as described in the microtitre screen

EXAMPLES 15 to 18

A 0.1% (w/w) solution of the fungicides under test was prepared in 50/50dioctylphthalate and dioctyladipate. Aliquots of 0.125, 0.25, 0.5, 2.0and 3.0 mls of each solution (to give 1.25, 2.5, 5, 20 and 30 ppmfungicide) was adjusted in volume to 3 mls by adding thedioctylphthalate/adipate mixture and then made up to 100 ml with PotatoDextrose Tryptone soya agar and homogenised. Plates were cast in petridishes and allowed to set. Each plate was then inoculated, using amulti-point applicator, with a 10⁵ spore suspension of AP, FS, PF and SBand a 10⁵ colony suspension of SW. The plates were incubated at 20° C.for 4 days and the MIC value determined. The results are given in Table2 below.

                  TABLE 2    ______________________________________               Fungi    Example           Substituent                     AP      FS    PP    SB    SW    ______________________________________    15     --        <1.25   <1.25 <2.25 <1.25 <1.25    16     6 Cl--    20      20    2.5   2.5   2.5    17     5 Cl--    <1.25   <1.25 <1.25 <1.25 5    18     5 F--     <1.25   <1.25 <1.25 <1.25 <1.25    A      SK        2.5     20    <1.25 2.5   2.5    B      DS        60      80    4.0   2.5   2.5    ______________________________________     Footnote to Table 2     SK = 2n-octylisothiazolin-3one     DS = 2,3,5,6tetrachloro-(4-methylsulphone)pyridine     AP = Aureobasidium pullulans     FS = Fusarium solani     PP = Pepicillium pinophylum     SB = Scopulariopsis brevicaulis     SW = Streptoverticillium waksmanii

EXAMPLES 19-22

The MIC of the following benzoxaborole derivatives was determined usingthe paint film protocol described hereinbefore. The values obtained aregiven in Table 3 below.

                  TABLE 3    ______________________________________               Organism    Example           Substituent                     PV      CH    AA    AP    SD    ______________________________________    19     --        1       4     2     2     1    20     5 F--     <0.25   0.5   <0.25 <0.25 <0.25    21     5 Cl--    <0.25   0.5   <0.25 <0.25 <0.25    22     5 Br--    2       4     2     1     2    C      SK        1       8     0.5   <0.25 8    D      TP        0.8     0.8   0.4   0.4   0.8    ______________________________________     Footnote to Table 3     SK = 2n-octylisothiazolin-3-one     TP = iodopropynylbutylcarbamate

Preparative Examples 23 to 58

Example 1 a) and b) was repeated using the equivalent weight ofbenzaldehyde and 3-fluorobenzaldehyde in place of the3-chlorobenzaldehyde used in Example 1a to obtain the analogous1,3-dihydro-1-hydroxy-2,1-benzoxaborole derivatives. These benzoxaborolederivatives were then reacted with an alkanolamine as described inExample 2 by replacing the ethanolamine with the equivalent amount ofalkanolamine.

The benzoxaborole esters obtained have formula 2 ##STR7##

The elemental analysis and/or melting points of the compounds obtainedare given in Table 4 below.

                                      TABLE 4    __________________________________________________________________________                                 Elemental Analysis (%)    Ex      R.sup.7         R.sup.3            R.sup.4              Y            mp °C.                                 Found      Theory    __________________________________________________________________________    23      H  H  H --(CH.sub.2).sub.2 --                           214-216                                 60.3 C                                     6.7 H                                        7.6 N                                            61.0 C                                                6.8 H                                                   7.9 N    24      H  H  H --(CH.sub.2).sub.3 --                           174-176                                 64.5 C                                     7.5 H                                        7.1 N                                            62.8 C                                                7.3 H                                                   7.3 N    25      H  H  H --(CH.sub.2).sub.4 --                           161-163                                 64.9 C                                     8.1 H                                        7.0 N                                            64.4 C                                                7.8 H                                                   6.8 N    26      5-Cl         H  H --(CH.sub.2).sub.3 --                           196-199    27      5-Cl         H  H --(CH.sub.2).sub.4 --                             169-171.5    28      5-Cl         Me H --(CH.sub.2).sub.2 --                           143-148    29      5-Cl         H  H --CH.sub.2 --CH(CH.sub.3)--                           191-194    30      5-Cl         H  H --CH(CH.sub.3)--CH.sub.2 --                           206-210    31      S-Cl         H  H --CH.sub.2 --C(CH.sub.3).sub.2 --                           172-175    32      H  Me H --(CH.sub.2).sub.2                           167-169                                 62.4 C                                     7.4 H                                        7.2 N                                            62.8 C                                                7.3 H                                                   7.3 N    33      H  H  H --CH.sub.2 C(CH.sub.3).sub.2 --                           176-178                                 61.5 C                                     7.4 H                                        5.3 N                                            64.4 C                                                7.8 H                                                   6.8 N    34      5-F         H  H --(CH.sub.2).sub.3 --                           186-187                                 62.6 C                                     6.1 H                                        5.5 N                                            62.6 C                                                6.2 H                                                   6.7 N    35      H  Me Me              --(CH.sub.2).sub.2 --                                 61.5 C                                     7.4 H                                        5.3 N                                            61.7 C                                                7.9 H                                                   6.5 N    36      5-F         Me H --(CH.sub.2).sub.2 --                           184-192                                 57.0 C                                     6.0 H                                        7.3 N                                            57.4 C                                                6.2 H                                                   6.7 N    37      5-F         H  H --(CH.sub.2).sub.2 --                           232-234                                 55.0 C                                     5.5 H                                        7.1 N                                            55.4 C                                                5.6 H                                                   7.2 N    38      5-F         H  H --CH.sub.2 --C(CH.sub.3).sub.2 --                           132-134                                 57.9 C                                     6.7 H                                        6.1 N                                            58.0 C                                                6.8 H                                                   6.2 N    39      5-F         H  H --(CH.sub.2).sub.4 --                           163-165                                 58.6 C                                     6.8 H                                        6.5 N                                            59.2 C                                                6.7 H                                                   6.3 N    40      H  tBu            H --(CH.sub.2).sub.2 --                           141-143                                 62.4 C                                     8.3 H                                        4.7 N                                            62.2 C                                                8.8 H                                                   5.6 N    41      H  Et H --(CH.sub.2).sub.2 --                           178-180                                 64.2 C                                     7.2 H                                        6.7 N                                            64.4 C                                                7 9 H                                                   6.8 N    42      H  nPr            H --(CH.sub.2).sub.2 --                           166-168                                 64.9 C                                     7.1 H                                        6.4 N                                            64.8 C                                                8.3 H                                                   6.3 N    43      H  nBu            H --(CH.sub.2).sub.2 --                           159-161                                 66.4 C                                     7.6 H                                        5.9 N                                            67.0 C                                                8.6 H                                                   6.0 N    44      H  nPe            H --(CH.sub.2).sub.2 --                           135-137                                 67.0 C                                     6.3 H                                        5.7 N                                            68.0 C                                                9.0 H                                                   5.7 N    45      H  H  H --CH(CH.sub.3)--CH.sub.2 --                           213-216                                 62.6 C                                     7.0 H                                        7.2 N                                            62.8 C                                                7.3 H                                                   7.3 N    46      5-Cl         H  H --CH--(CH.sub.2 CH.sub.3)CH.sub.2 --                             213-214.5    47      5-Cl         H  H --CH.sub.2 --CH(CH.sub.2 CH.sub.3)--                           187.5-169 `    48      H  H  H --CH.sub.2 CH(CH.sub.3)--                           173-175                                 64.5 C                                     7.5 H                                        6.4 N                                            62.B C                                                7.3 H                                                   7.3 N    49      H  H  H --CH.sub.2 CH(CH.sub.2 CH.sub.3)--                           20S-207                                 64.4 C                                     7.5 H                                        6.8 N                                            64.4 C                                                7.9 H                                                   6.6 N    50      H  H  H --CH(CH.sub.2 CH.sub.3)CH.sub.2 --                           207-210                                 64.2 C                                     7.9 H                                        7.1 N                                            64.4 C                                                7.9 H                                                   6.6 N    51      H  H  H --CH.sub.2 CH((CH.sub.2).sub.3 CH.sub.3)--                           166-191                                 66.8 C                                     8.7 H                                        6.4 N                                            67.0 C                                                6.6 H                                                   6.0 N    52      H  H  H --CH.sub.2 CH(CH.sub.2 CH(CH.sub.3).sub.2)--                           204-207                                 66.6 C                                     7.6 H                                        6.0 N                                            67.0 C                                                6.6 H                                                   6.0 N    53      H  H  H --CH.sub.2 CH((CH.sub.2).sub.2 CH.sub.3)--                           210-213                                 66.4 C                                     6.4 H                                        6.5 N                                            65.6 C                                                8.3 H                                                   6.4 N    54      H  H  H --CH.sub.2 CH((CH.sub.2).sub.2 SCH.sub.3)--                           174-17S                                 57.4 C                                     6.1 H                                        5.8 N                                            57.4 C                                                7.2 H                                                   5.6 N                                        13.0 S     12.8 S    55      5-F         Et H --(CH.sub.2).sub.2 --                           186-169                                 59.2 C                                     6.6 H                                        6.3 N                                            59.2 C                                                6.1 H                                                   6.1 N    56      5-F         H  H --CH.sub.2 CH(CH.sub.2 CH.sub.3)--                           212-214                                 59.0 C                                     6.5 H                                        6.2 N                                            59.2 C                                                6.6 H                                                   6.3 N    57      5-F         H  H --CH(CH.sub.2 CH.sub.3)CH.sub.2 --                           205-208                                 56.3 C                                     6.6 H                                        6.2 N                                            59.2 C                                                6.6 H                                                   6.3 N    58      5-F         Pr H --(CH.sub.2).sub.2 --                           162-184                                 60.8 C                                     7.4 H                                        5.8 N                                            60.6 C                                                7.2 H                                                   5.9 N    __________________________________________________________________________

Preparative Examples 59-78 (except 65 and 71)

These oxaboroles where prepared by an analogous method to that describedin Example 1 a) and b) by replacing the 3-chlorobenzaldehyde with anequivalent amount of appropriate aldehyde. The benzoxaborole derivativesobtained have general formula ##STR8##

The elemental analysis and/or melting points of such compounds arelisted in Table 5 below.

                                      TABLE 5    __________________________________________________________________________                        Elemental Analysis (%)    Example         R.sup.8               R.sup.9                  mp °C.                        Found      Theory    __________________________________________________________________________    59   6-Cl  H  156-158                        49.5 C                            3.5 H                               21.0 N                                   49.8 C                                       3.5 H                                           21.0 N    60   5-PhO H  101-105    61   5-C(CH.sub.3).sub.3               H  119-123    62   4,5 fused Ph               H    137-139.5    63   5,6 fused Ph               H    161-163.5    64   5-F   H  127-129                        54.9 C                            4.2 H  55.2 C                                       3.9 H    65   H     Ph 145-147    66   5-Cl  H  150-155                        49.9 C                            3.5 H                               20.8 N                                   49.8 C                                       3.5 H                                           21.0 N    67   5-CF3 H        47.6 C                            3.1 H  47.5 C                                       2.9 H    68   5-Br  H        39.4 C                            2.7 H                               39.6 Br                                   39.4 C                                       2.8 H                                           37.6 Br    69   4-F   H        54.8 C                            4.2 H                               6.9 B                                   55.2 C                                       3.95 H                                           7.2 B                            8.9 F      12.5 F    70   6-F   H        54.5 C                            4.1 H                               7.1 B                                   55.2 C                                       3.95 H                                           7.2 B                            8.5 F      12.5 F    71   H     --CN                  114-115                        59.0 C                            3.5 H                               8.6 N                                   60.3 C                                       3.8 H                                           8.8 N    72   4-CH.sub.3, 5-F               H  162-163                        57.4 C                            4.4 H                               5.9 B                                   57.8 C                                       4.8 H                                           6.6 B    73   5,6 diF               H  148-151                        49.2 C                            3.0 H                               6.2 B                                   49.4 C                                       2.9 H                                           6.4 B    74   5-CH.sub.3 O               H  122-124          58.5 C                                       5.4 H                                           6.7 B    75   7-F   H  132-134          55.0 C                                       4.0 H                                           7.1 B    76   4,7 diF               H    77   6,7 diF               H    78   5,7 diF               H    __________________________________________________________________________

Preparative Example 65 Preparation of3-phenyl-1,3-dihydro-1-hydroxy-2,1-benzoxaborole

a) Preparation of benzophenone p-toluenesulphonylhydrazone

Benzophenone (15.0 parts, 0.082M ex Fluka) was stirred at reflux withp-toluene sulphonylhydrazine (15.33 parts, 0.082M ex Aldrich) in ethanol(125 ml) for 10 hours. Gradually a pale yellow solution formed fromwhich the hydrazone gradually precipitated. After cooling to 20° C.,diethylether (20 ml) was added and the hydrazone filtered and washedwith ether. The hydrazone was obtained as a white powder (24.0 parts;83% theory) mp 184°-6° C.

Proton NMR Analysis

2.44 (s, 3H), 7.0-7.18 (m, 2H), 7.27-7.38 (m, 5H)

2.42-2.48 (m, 2H), 7.48-7.55 (m, 4H), 7.56 (s, H)

7.86 (d, 2H).

b) Preparation of Diazaborine derivative

Anhydrous ferric chloride (0.75 parts) was suspended in drydichloroethane (75 ml) and solutions of boron tribromide (131 ml of Msolution in dichloromethane, 0.131M ex Aldrich) and the hydrazone from(a) above (15.0 parts, 0.043M in dry dichloroethane, 200 ml) addedsimultaneously at 20° C. over 15 mins with stirring under nitrogen. Thetemperature rose by about 2° C. The dark red reaction mix was stirred atreflux for 41/2 hours to remove the hydrogen bromide.

The reactants were then cooled and drowned into ice (500 parts) andwater (500 parts). The organic phase was separated and extracted withaqueous sodium hydroxide solution. The aqueous layer was then separatedand the pH adjusted to pH 3 by addition of concentrated hydrochloricacid. This aqueous layer was extracted with dichloromethane which wasthen separated, dried over magnesium sulphate and the solvent removed togive the product as a cream solid. Yield=3.83 parts (24% theory) mp239°-42° C.

Proton NMR Analysis

35 2.44 (s, 3H), 7.33 (d, 2H), 7.37-7.52 (m, 5H), 7.44 (s, H),

7.55-7.71 (m, 3H), 7.95 (d, 2H), 8.25-8.35 (m, H).

c) Preparation of title compound

The diazaborine from (b) (2.6 parts) was stirred at reflux in 10%aqueous potassium hydroxide solution (100 ml) containing ethanol (50 ml)for 41/2 hours. The solution was then cooled, washed withdichloromethane and the pH adjusted to pH 3 with concentratedhydrochloric acid. A suspension formed which was extracted intodichloromethane. After removal of the solvent, a pale cream solid wasobtained which was found to be a mixture of starting material andproduct. This was purified by preparative column chromatography using asilica column developed with dichloromethane.

After removing the solvent by evaporation, the product was obtained as awhite solid (0.49 parts; 24% theory) mp=145°-7° C.

Proton NMR Analysis

6.14 (s, H), 7.15 (d, H), 7.21-7.46 (m, 7H),

7.83 (d, H), 8.51 (s, H).

Preparative Example 71 Preparation of3-cyano-1,3-dihydro-1-hydroxy-2,1-benzoxaborole

a) Preparation of 2-formylphenylboronic acid (Ref JACS 86 1964 p435)

o-Tolyl boronic acid (10 parts; 0.0714M ex Aldrich) andN-bromosuccinimide (30.13 g; 0.169M ex Aldrich) were dried at 110° C.for 16 hours. Both these reactants were added to carbon tetrachloride(450 ml) and 50 ml of the solvent distilled off to remove any remainingwater. Benzoyl peroxide (1.5 parts) was added and the reactants stirredunder reflux for 6 hours. After cooling, cyclohexene (1.25 parts) wasadded to remove any bromine and the solution screened to removesuccinimide. The product was then extracted with 15% aqueous potassiumhydroxide solution (4×35 ml). These aqueous extracts were combined andacidified to about pH 4 with concentrated hydrochloric acid. The productwas then extracted into diethylether (3×200 ml). The combined etherextracts were then dried over magnesium sulphate and the etherevaporated. Finally, the product was recrystallised from water.Yield=1.69 parts (15.3% theory) mp 122°-4° C.

Elemental Analysis

Found 55.3% C, 4.7% H

Theory 56.0% C, 4.7% H

b) Preparation of title compound (Ref JOC 29 1964 p2172)

2-formyl phenyl boronic acid (1.0 parts, 0.007M) was added to an aqueoussolution of sodium cyanide (0.35 parts) in water (20 ml) at 20° C. withstirring. After 15 mins the reactants were cooled to 5° C. and carefullyneutralised to pH 5 with concentrated hydrochloric acid. The resultantwhite precipitate was filtered and recrystallised from water (25,ml).The product was dried over calcium chloride. Yield=0.29 parts (26%theory) mp=114°-5° C.

Elemental Analysis

Found 59.0%, 3.5% H, 8.6% N

Theory 60.3%, 2.8% H, 8.8% N.

Preparative Examples 79 and 80

Example 2 was repeated except that the ethanolamine was replaced by anequivalent amount of 8-hydroxyquinoline to give the benzoxaborole ofExample 79. Example 80 was obtained by replacing the boronophthalide ofExample 79 with the equivalent amount of the 5-fluoro analogue. Theanalytical data and/or melting point is given in Table 6 below for thebenzoxaborole of formula ##STR9##

                  TABLE 6    ______________________________________    Ex-    am-              Elemental Analysis (%)    ple  R.sup.10                mp °C.                         Found       Theory    ______________________________________    79   H      189-190  73.4 C                               4.4 H                                    5.4 N                                         73.6 C                                               4.6 H                                                    5.4 N    80   F      118-119                  68.8 C                                               3.9 H                                                    5.0 N    ______________________________________

Preparative Examples 81-90

Preparative examples 23-58 were again repeated using equivalent amountsof various aldehydes and alkanolamines to obtain further benzoxaboroleesters of formula 2 ##STR10##

The melting points of these compounds are given in Table 7 below.

                  TABLE 7    ______________________________________    Example           R.sup.7   R.sup.3                           R.sup.4                               Y           mp °C.    ______________________________________    81     5 Cl      H     H   (CH.sub.2).sub.2                                           205-208    82     5 PhO     H     H   (CH.sub.2).sub.2                                           175-179    83     5 C(CH.sub.3).sub.3                     H     H   (CH.sub.2).sub.2                                           165-168    84     5 Cl      H     H   CH(Ph)CH.sub.2                                             203-206.5    85     5 Cl      H     H   CH.sub.2 CH(Ph)                                           59-66    86     5 Cl      H     H   COCH.sub.2  216-219    87     5 Cl      H     H   CH.sub.2 CH(CH.sub.2 Ph)                                           202.6-205    88     4,5 fused Ph                     H     H   (CH.sub.2).sub.2                                           228-230    89     5,6 fused Ph                     H     H   (CH.sub.2).sub.2                                           204-206    90     5 Cl      H     H                                ##STR11##  212-213    ______________________________________

Preparative Example 91 Preparation of5-methoxy-1,3-dihydro-1-hydroxy-2,1-benzoxaborole

2-bromo-5-methoxybenzylalcohol (6.5 parts; 0.03M) was dissolved in dryTHF (100 ml) and cooled to -78° C. n-Butyl-lithium (26.4 ml of a 2.5Msolution in hexanes ex Aldrich, 0.066M) was added over 20 minutes withstirring under a nitrogen blanket and keeping the temperature below -60°C. After stirring for a further hour at -70° C. HPLC showed the reactionto be incomplete with 20% starting material remaining. A further aliquotof n-butyl-lithium in hexanes (5 ml; 0.0125M) was added and thereactants allowed to warm to -50° C.

Tributylborate (17.8 ml; 0.066M) was then added at between -70° and -50°C. with stirring under a nitrogen blanket and the reactants allowed towarm to about 20° C. Water (20 ml) was added and the pH adjusted to 10with hydrochloric acid. After washing with diethylether, the pH of theaqueous phase was adjusted to pH 1-2 with hydrochloric acid and washedwith diethyl ether. The ether extract was washed with aqueous saturatedbrine, dried over anhydrous magnesium sulphate and the ether evaporatedto leave the product as a pale oil (3.7 parts). This was slurried withwater containing a little methanol whereupon a pinkish-white solidseparated which was filtered, washed with water and dried (2.0 parts)mp=110°-115° C. after recrystallisation from aqueous methanol.

Preparative Example 92 Preparation of7-fluoro-1,3-dihydro-1-hydroxy-2,1-benzoxaborole

3-fluorobenzyl alcohol (3.5 parts; 0.028M) was stirred in THF (100 ml)containing tetramethylene ethylenediamine (10.2 ml; 0.067M). Aftercooling to -78° C., sec-butyl-lithium (77 ml of 0.8M solution incyclohexane ex Aldrich; 0.061M) was slowly added over 45 min at between-78° and -65° C. with stirring under a nitrogen blanket. After 1 hour at-78° C., tributyl borate (16.78 ml; 0.061M) was added dropwise and thereactants stirred under nitrogen for 16 hrs allowing the temperature toslowly raise to 20° C. Dilute hydrochloric acid was added to bring thepH to about 12 and the aqueous phase separated and washed withdiethylether. The pH of the aqueous phase was then acidified to about pH2 with hydrochloric acid and extracted with ether (3×100 ml). Theseether extracts were washed with saturated brine, dried over magnesiumsulphate and the ether evaporated whereupon the product separated as apale solid (2.6 parts; 62% theory) mp=132°-134° C. afterrecrystallisation from aqueous methanol.

Preparative Example 93 Preparation of ##STR12## a) Preparation of3-bromo-2-formylthiophene Ref Acta Chem Scand 22 (1968) 4 1354

2,3-dibromothiophene (14 parts, 0.058M ex Lancaster Chemicals) wasweighed into a reaction vessel equipped with a rubber septum. Drydiethyl ether (112 mls) was added by syringe through under a nitrogenblanket and cooled to -70° C. n-Butyl lithium (26.8 mls of 2.5M solutionin hexanes ex Aldrich) was slowly added over 20 mins. After stirring at-70° C. for 1/2 hour, dimethylformamide (6.3 parts) in diethyl ether wasadded over 5 mins. The reactants were allowed to warm to 20° C., then100 mls water was added with stirring. The ether solution was thenwashed with N hydrochloric acid, aqueous bicarbonate and water. Theether solution was then dried over magnesium sulphate and the etherevaporated to leave an orange/brown oil (12.32 parts). This oil wasdistilled at 0.05 mm Hg and 680C to give a straw-coloured oil (4.5parts). This oil was dissolved in dichloromethane and evaporated ontosilica. This silica was formed into a column and the product separatedby flash chromatography. The silica column was developed by washing withhexane containing increasing amounts of dichloromethane. The product waseluted in fractions containing from 10-30% dichloromethane in hexane.

Yield=4.05 parts.

Elemental Analysis

Found 32.0% C, 1.8% H, 16.7% S

Theory 31.4% C, 1.6% H, 16.8% S

b) Preparation of 2-(3-bromo-2-thienyl)-1,3-dioxolane

3-bromo-2-formylthiophene (3.89 parts, 0.02M) was heated at reflux withdry ethyleneglycol (1.6 parts) toluene (25 parts) and p-toluenesulphonic acid (0.1 parts) in a vessel equipped with a Dean and Starkseparator for 16 hours. The reactants were then cooled and evaporatedinto silica. The silica was formed into a column which was thendeveloped by elution with hexane containing increasing amounts ofdichloromethane. The product was obtained from fractions containing10-60% dichloromethane as a pale straw-coloured oil (4.42 parts).

Elemental Analysis

Found 35.6% C, 3.1% H, 13.6% S

Theory 35.8% C, 3.0% H, 13.7% S

c) Preparation of 2-formyl-3-thiopheneboronic acid

Butyl lithium (7.9 ml of 2.5M solution in hexanes ex Aldrich) was slowlyadded to a solution of the dioxolane from (b) (4.28 parts, 0.018M) indry diethylether with stirring at -70° C. under a nitrogen blanket.After stirring for 15 mins butyl borate (6 mls ex Aldrich) dissolved inethylether (20 ml) was slowly added at -70° C. The reactants werestirred for a further 4 hours at -700C and then warmed to 20° C. 25 ml Nhydrochloric acid was added and the reactants stirred for 1 hour at 20°C. The ether layer was then separated and extracted with N aqueoussodium carbonate solution (3×10 ml). This aqueous carbonate solution wasslowly acidified whereupon the product separated and was filtered anddried.

Yield=0.89 parts.

Elemental Analysis

Found 36.6% C, 3.0% H, 19.6% S

Theory 38.5% c, 3.2% H, 20.5% S

d) Preparation of title compound

The boronic acid from (c) (0.5 parts, 0.0032M) was dissolved in ethanoland sodium borohydride (30 mg ex Aldrich) added with stirring at 20° C.After 30 mins the reaction mass was evaporated onto silica which wasformed into a column and developed with hexane containing increasingamounts of dichloromethane and then dichloromethane containingincreasing amounts of methanol. The product was obtained from fractionsof dichloromethane containing 3-4% methanol. After evaporating thesolvent, the product was recrystallised from toluene.

Yield=0.13 part mp 203°-4° C.

Elemental Analysis

Found 45.5% C, 3.2% H, 23.3% S

Theory 45.8% c, 3.1% H, 26.4% S

The microbiological test data for this compound is

    ______________________________________    AN   CA      AP     GR    PP   EC    PA   SA    BS    ______________________________________    N    N       N      N     N    N     N    100   25    ______________________________________

The legands are explained in the footnote to Table 8.

Microbiological Examples 23 to 58

The MIC of the following benzoxaborole esters was determined against themicro-organisms indicated in Table 8 for the compounds of formula##STR13##

R⁷ represents one or more substituents in the phenyl ring.

The test method employed was as follows.

The bacterial inoculum consisted of 24 hour cultures of the organismsgrown in Oxoid Nutrient broth, subcultured daily and incubated at 37° C.

Spore suspensions of each of the test fungi were prepared in thefollowing manner. To 250 ml conical flasks containing well sporulatingcultures of the fungi, growing on Oxoid Malt extract agar, a number ofsterile 3 mm glass beads and approximately 50 ml of a sterile solutionof 0.01% v/v of polyoxyalkylene (20) sorbitan mono-oleate (ex ICI asTween 80 --Tween is a registered trademark) in water were added. Eachflask was swirled so that the beads removed the spores and the resultingsuspension was poured into a sterile 100 gm medical flat bottlecontaining approximately 50 ml of the sterile 0.01% v/v solution ofTween 80. The suspension was storable for up to four weeks at 40° C.

In the microbiological testing, the oxaborazoles were tested at 5, 25and 100 ppm against the bacteria, yeast and fungi listed in the footnoteto Table

                                      TABLE 8    __________________________________________________________________________                                    Fungi      Bacteria    Example         R.sup.7            R.sup.3                   R.sup.4                       Y            AN CA                                         AP                                           GR                                             PP                                               EC PA SA BS    __________________________________________________________________________    23   H  H      H   --(CH.sub.2).sub.2 --                                    5  5 5 5 5 25 25 25 25    24   H  H      H   --(CH.sub.2).sub.3 --                                    5  5 5 5 5 25 25 25 25    25   H  H      H   --(CH.sub.2).sub.4 --                                    5  5 5 5 5 25 25 25 25    26   5-Cl            H      H   --(CH.sub.2).sub.3 --                                    5  5 5 5 5 25 25 100                                                        25    27   5-Cl            H      H   --(CH.sub.2).sub.4 --                                    5  5 5 5 5 25 25 N  25    28   5-Cl            --CH.sub.3                   H   --(CH.sub.2).sub.2 --                                    5  5 5 5 5 25 25 N  25    29   5-Cl            H      H   --CH.sub.2 --CH(CH.sub.3)--                                    5  5 5 5 5 25 25 100                                                        25    30   5-Cl            H      H   --CH(CH.sub.3)--CH.sub.2 --                                    5  5 5 5 5 25 25 N  25    31   5-Cl            H      H   --CH.sub.2 --C(CH.sub.3).sub.2 --                                    5  5 5 5 5 25 25 N  25    32   H  --CH.sub.3                   H   --(CH.sub.2).sub.2 --                                    5  5 5 5 5 25 25 100                                                        25    33   H  H      H   --CH.sub.2 C(CH.sub.3).sub.2 --                                    5  5 5 5 5 25 25 100                                                        25    34   5-F            H      H   --(CH.sub.2).sub.2 --                                    5  5 5 5 5 25 25 100                                                        25    35   H  --CH.sub.3                   --CH.sub.3                       --(CH.sub.2).sub.2 --                                    5  5 5 5 5 100                                                  25 N  25    36   5-F            --CH.sub.3                   H   --(CH.sub.2).sub.2 --                                    5  5 5 5 5 25 25 25 25    37   5-F            H      H   --(CH.sub.2).sub.2 --                                    5  5 5 5 5 25 25 100                                                        25    38   5-F            H      H   --CH.sub.2 --C(CH.sub.3).sub.2 --                                    5  5 5 5 5 25 25 100                                                        25    39   5-F            H      H   --(CH.sub.2).sub.4 --                                    5  5 5 5 5 100                                                  100                                                     N  25    40   H  --C(CH.sub.3)                   H   --(CH.sub.2).sub.2 --                                    5  5 5 5 5 25 25 25 25    41   H  --CH.sub.2 CH.sub.3                   H   --(CH.sub.2).sub.2 --                                    5  5 5 5 5 25 25 25 25    42   H  --(CH.sub.2).sub.2 CH.sub.3                   H   --(CH.sub.2).sub.2 --                                    5  5 5 5 5 25 25 25 25    43   H  --(CH.sub.2).sub.3 CH.sub.3                   H   --(CH.sub.2).sub.2 --                                    5  5 5 5 5 25 25 25 25    44   H  --(CH.sub.2).sub.4 CH.sub.3                   H   --(CH.sub.2).sub.2 --                                    5  25                                         5 5 5 N  100                                                     25 100    45   H  H      H   --CH(CH.sub.3)--CH.sub.2 --                                    5  5 5 5 5 100                                                  N  25 25    46   5-Cl            H      H   --CH--(CH.sub.2 CH.sub.3)CH.sub.2 --                                    5  5 5 5 5 100                                                  N  25 N    47   5-Cl            H      H   --CH.sub.2 --CH(CH.sub.2 CH.sub.3)--                                    5  5 5 5 5 25 N  25 N    48   H  H      H   --CH.sub.2 CH(CH.sub.3)--                                    5  5 5 5 5 25 N  25 100    49   H  H      H   --CH.sub.2 CH(CH.sub.2 CH.sub.3)--                                    5  5 5 5 5 25 N  25 25    50   H  H      H   --CH(CH.sub.2 CH.sub.3)CH.sub.2 --                                    5  5 5 5 5 100                                                  N  25 100    51   H  H      H   --CH.sub.2 CH((CH.sub.2).sub.3 CH.sub.3)--                                    5  5 5 5 5 100                                                  N  25 100    52   H  H      H   --CH.sub.2 CH(CH.sub.2 CH(CH.sub.3).sub.2)--                                    5  5 5 5 5 100                                                  N  25 100    53   H  H      H   --CH.sub.2 CH((CH.sub.2).sub.2 CH.sub.3)--                                    5  5 5 5 5 25 100                                                     25 25    54   H  H      H   --CH.sub.2 CH((CH.sub.2).sub.2 SCH.sub.3)--                                    5  5 5 5 5 25 100                                                     100                                                        25    55   5-F            --CH.sub.2 CH.sub.3                   H   --(CH.sub.2).sub.2 --                                    5  5 5 5 5 25 N  100                                                        25    56   5-F            H      H   --CH.sub.2 CH(CH.sub.2 CH.sub.3)--                                    5  5 5 5 5 25 N  100                                                        25    57   5-F            H      H   --CH(CH.sub.2 CH.sub.3)CH.sub.2 --                                    5  5 5 5 5 25 N  100                                                        25    58   5-F            --(CH.sub.2).sub.2 CH.sub.3                   H   --(CH.sub.2).sub.2 --                                    5  5 5 5 5 25 N  100                                                        25    Control         H  --     --  --           25 25                                         5 5 5 100                                                  N  N  25    __________________________________________________________________________     Footnote to Table 8     N = no activity at 100 ppm level     Control = boronophthalide     AN = Aspergillus niger     AP = Aureobasidium pullulans     CA = Candida albicans     GR = Gliocladium roseum     PP = Penicillium pinophylum     BS = Bacillus subtilis     EC = Escherichia coli     PA = Pseudomonas aeruginosa     SA = Staphylococcus aureus

Microbiological Examples 59 to 78

Examples 23 to 58 were repeated and the MIC value for benzoxaboroles ofthe following structure determined. ##STR14##

R⁸ represents one or more substituents in the phenyl ring.

The results are given in Table 9 below.

                                      TABLE 9    __________________________________________________________________________                  Fungi          Bacteria    Example         R.sup.8               R.sup.9                  AN CA AP GR PP EC PA SA BS    __________________________________________________________________________    59   6-Cl  H  100                     100                        100                           5  5  N  N  N  N    60   5-PhO H  5  5  5  5  5  25 N  25 25    61   5-C(CH.sub.3).sub.3               H  100                     100                        100                           100                              100                                 100                                    N  100                                          100    62   4,5 fused Ph               H  25 25 25 25 25 100                                    N  25 25    63   5,6 fused Ph               H  25 25 25 25 25 25 N  100                                          100    64   5-F   H  5  5  5  5  5  100                                    N  N  25    65   H     Ph N  N  100                           100                              100                                 N  N  N  N    66   5-Cl  H  5  5  5  5  5  N  N  N  N    67   5-CF.sub.3               H  25 25 25 25 25 N  N  N  25    68   5-Br  H  5  25 5  5  5  100                                    100                                       25 25    69   4-F   H  100                     100                        25 25 100                                 100                                    N  100                                          25    70   6-F   H  100                     25 25 25 25 25 N  100                                          25    71   H     --CN                  N  N  N  N  N  N  N  N  N    72   4-CH.sub.3, 5-F               H  N  N  N  N  N  N  N  N  N    73   5,6 diF               H  25 25 25 5  5  25 N  N  25    74   5-CH.sub.3 O               H  250                     125                        62.5                           125                              250                                 250                                    250                                       250                                          500    74   7-F   H  16 16 16 31 16 125                                    250                                       125                                          8    76   4,7 diF               H    77   6,7 diF               H    78   5,7 diF               H    Control         H     H  25 25 5  5  5  ioO                                    N  N  25    __________________________________________________________________________     Footnote to Table 9     Control is boronophthalide (R.sup.8 = R.sup.9 = H)

Examples 79 and 80

Examples 23 to 58 were repeated and the MIC values for benzoxaboroles ofthe following structure determined ##STR15##

The results are given in Table 10 below.

                  TABLE 10    ______________________________________            Fungi          Bacteria    Example           R.sup.10                  AN     CA  AP   GR  PP   EC   PA   SA  BS    ______________________________________    79     H      25     25  25   25  25   100  100  25  25    80     F      5      5   5    5   5    25   25   25  25    ______________________________________

Plastics Deteriogen Examples 23-34, 36-58, 68 and 80 Determination ofActivity against plastics deteriogens

Examples 15 to 18 were repeated using certain of the examples listed inExamples 23 to 78. The activity of the various benzoxaboroles is listedin Table 11 below. The example reference numbers listed in Table 8 and 9are retained.

                  TABLE 11    ______________________________________    Example  AP        FS     PF      SB   SW    ______________________________________    23       1.25      1.25   1.25    1.25 2.5    24       1.25      1.25   2.5     2.5  5.0    25       1.25      2.5    2.5     2.5  20    26       1.25      1.25   1.25    1.25 2.5    27       1.25      1.25   1.25    1.25 2.5    28       1.25      1.25   1.25    1.25 1.25    29       1.25      1.25   1.25    1.25 1.25    30       1.25      1.25   1.25    1.25 1.25    31       1.25      1.25   1.25    1.25 1.25    32       1.25      1.25   1.25    1.25 1.25    33       1.25      1.25   1.25    1.25 1.25    34       1.25      1.25   1.25    1.25 1.25    36       1.25      1.25   1.25    1.25 5.0    37       1.25      1.25   1.25    1.25 5.0    38       1.25      1.25   1.25    1.25 5.0    39       1.25      1.25   1.25    1.25 5.0    40       2.5       1.25   1.25    1.25 1.25    41       1.25      1.25   1.25    1.25 1.25    42       2.5       2.5    1.25    1.25 1.25    43       2.5       2.5    1.25    1.25 1.25    44       1.25      1.25   1.25    1.25 1.25    45       1.25      1.25   1.25    1.25 1.25    46       1.25      1.25   1.25    1.25 1.25    47       1.25      1.25   1.25    1.25 1.25    48       1.25      1.25   1.25    1.25 1.25    49       1.25      1.25   1.25    1.25 1.25    50       1.25      1.25   1.25    1.25 1.25    51       1.25      1.25   1.25    1.25 1.25    52       1.25      1.25   1.25    1.25 1.25    53       1.25      1.25   1.25    1.25 1.25    54       5.0       1.25   5.0     1.25 5.0    55       2.5       1.25   1.25    1.25 1.25    56       1.25      1.25   1.25    1.25 1.25    57       1.25      1.25   1.25    1.25 1.25    58       1.25      1.25   1.25    1.25 1.25    68       5.0       5.0    1.25    1.25 1.25    80       1.25      1.25   1.25    1.25 1.25    Contro1 1             2.5       2.5    2.5     2.5  20.0    Control 2             2.5       20     2.5     1.25 1.25    ______________________________________     Footnote to Table 11     Control 1 is boronophthalide     Control 2 is 2n-octylisothiazolin-3-one

We claim:
 1. A method for the protection of a medium susceptible tomicrobial attack by the treatment of the medium with an effective amountof an oxaborole of formula (1) ##STR16## or a salt thereof: whereinA andD together with the carbon atoms to which they are attached form a 5, 6,or 7-membered fused ring which may be substituted by C₁₋₆ -alkyl, C₁₋₆-alkoxy, hydroxy, halogen, nitro, nitrile, amino, amino substituted byone or more C₁₋₆ -alkyl groups, , carboxy, acyl, aryloxy, carbonamido,carbonamido substituted by C₁₋₆ -alkyl, sulphonamido or trifluoromethylor the fused ring may link two oxaborole rings; X is a group --CR¹ R²wherein R¹ and R² are each, independently, hydrogen, C₁₋₆ -alkyl,nitrile, nitro, aryl, aralkyl or R¹ and R² together with the carbon atomto which they are attached form an alicyclic ring; and R is hydrogen,C₁₋₁₈ -alkyl, (C₁₋₁₈ -alkyl substituted by C₁₋₆ -alkoxy, C₁₋₆-alkylthio, hydroxy, amino, amino substituted by C₁₋₁₈ -alkyl, ,carboxy, aryl, aryloxy, carbonamido, ( carbonamido substituted by C₁₋₆-alkyl, aryl or aralkyl), aralkyl, aryl, heteroaryl, cycloalkyl, C₁₋₁₈-alkyleneamino, C₁₋₁₈ -alkyleneamino substituted by phenyl, C₁₋₆ -alkoxyor C₁₋₆ -alkylthio, carbonyl alkyleneamino or a radical of formula (2)##STR17## wherein A, D and X are as defined hereinbefore except forboronophthalide.
 2. A method as claimed in claim 1 wherein A and Dtogether with the carbon atoms to which they are attached form a fusedphenyl ring.
 3. A method as claimed in either claim 1 or claim 2 whereinthe fused ring is substituted by halogen.
 4. A method as claimed inclaim 3 wherein R is hydrogen.
 5. A method as claimed in claim 1 whereinthe heteroaryl substituent represented by R is quinolinyl.
 6. A methodas claimed in claim 1 wherein the oxaborole is a compound of formula 3##STR18## wherein A, D and X are as defined in claim 1;Y is a divalentalkylene linking group containing up to 18 carbon atoms or a divalentalkylene linking group containing up to 18 carbon atoms which issubstituted by phenyl, C₁₋₆ alkoxy, C₁₋₆ -alkylthio; carbonyl alkyleneamino; and R³ and R⁴ are each, independently, hydrogen, C₁₋₁₈ -alkyl orphenyl or R³ together with Y or part of Y forms a 5-, 6- or 7-memberedring containing the nitrogen atom.
 7. A method as claimed in claim 5wherein the oxaborole is a compound of formula 4 ##STR19## wherein A, Dand X are as defined in claim 1;n is 1, 2 or 3; R³ is hydrogen, C₁₋₁₈-alkyl or phenyl; and R⁵ and R⁶ are each, independently, hydrogen, alkylcontaining up to a total of 16 carbon atoms or phenyl.
 8. A method asclaimed in claim 7 wherein the medium is a paint film or a plasticsmaterial.
 9. A compound of formula (1) ##STR20## or a salt thereofwherein A, D, R and X are as defined in claim 1 except for1,1'-oxybis;
 1. 1'-oxybis; 3,7-dihydro-1,5-dihydroxy-1H, 3H-benzo bisoxaborole; boronophthalide and boronophthalide containing the followingsubstituent(s):-6-nitro-, 6-amino-, 7-methyl-, 6-(NN-dimethylamino)-,5-(NN-dimethylamino)-, 4-bromo-, 6-methyl, 1-benzyloxy-,1-cyclohexyloxy-, 1-ethoxy-, 3-methyl and 3-cyano.
 10. A compound asclaimed in claim 9 which is of formula 3 ##STR21## wherein A, D and Xare as defined in claim 1;R³ and R⁴ are each, independently, hydrogen,C₁₋₁₈ -alkyl or phenyl or the group --NR³ R⁴ together with Y or part ofY forms a 5-, 6- or 7-membered ring containing the nitrogen atom; and Yis as defined in claim
 6. 11. A compound as claimed in either claim 9 orclaim 10 wherein the fused ring formed by A and D together with thecarbon atoms to which they are attached is a phenyl ring.
 12. A compoundas claimed in claim 11 which is an ester derived from 5- or 6-chloro, 5-or 6-bromo or 5- or 6-fluoro benzoxaborole.
 13. A composition comprisinga carrier and an oxaborole of formula 1 ##STR22## or a salt thereof:wherein A, D, X and R are as defined in claim 1 except where theoxaborole is boronophthalide.
 14. A composition as claimed in claim 13wherein the carrier is a paint film or a plastics material.
 15. Acomposition as claimed in claim 14 wherein the plastics material isplacticised PVC or polyurethane.
 16. A composition as claimed in claim13 wherein the carrier is a stabiliser or plasticiser for a plasticsmaterial.
 17. A composition as claimed in claim 16 wherein thestabiliser or plasticiser is dioctylphthalate, dioctyl adipate orexpoxidised soya bean oil.
 18. A process for making an oxaborole offormula 1 wherein A and D together with the carbon atoms to which theyare attached form a fused phenyl ring which comprises reacting ono-substituted halogeno toluene with magnesium or alkyl-lithium in ainert solvent and reacting the Grignard reagent or aryl lithium soformed with a borate ester to obtain a toluene boronic acid which isthen reacted with a brominating agent followed by hydrolysis to give ahydroxymethylbenzene boronic acid and cyclising the boronic acid underacid conditions to give a benzoxaborole.
 19. A process for making anoxaborole of formula 1 wherein A and D together with the carbon atoms towhich they are attached form a fused phenyl ring which comprisesreacting an optionally substituted benzaldehyde withp-toluenesulphonylhydrazide in an inert solvent followed by reactionwith boron tribromide and catalyst to give a1,2-dihydro-1-hydroxy-2-(4-methylphenylsulphonyl)-2,3,1-benzodiazaborinewhich is then hydrolysed and cyclised to form a benzoxaborole.
 20. Aprocess for making an oxaborole ester as claimed in claim 10 whichcomprises reacting an oxaborole of formula 1 where R is hydrogen with anamino-aliphatic carboxylic acid, alkanolamine or 8-hydroxyquinoline inan inert solvent at 25°-125° C.
 21. A process for making an oxaborole offormula 1 wherein A and D together with the carbon atoms to which theyare attached form a fused aromatic ring which comprises reacting anaromatic compound containing a --CH₂ OH group with alkyl or aryl-lithiumand an organo-borate in a dry inert liquid.
 22. A process as claimed inclaim 21 wherein the aromatic compound containing a CH₂ OH group alsocontains one or more further substituents which are ortho-lithiationactivating groups.
 23. A process for making an oxaborole of formula 1wherein A and D together with the carbon atoms to which they areattached form a fused aromatic ring which comprises reacting an aromaticcompound containing a --CH₂ OH group and an ortho chloro or fluoro groupwith alkyl or aryl lithium and an organo-borate in an inert organicliquid.